The use of polymer implants for drug delivery to brain tumors has prolonged survival in patients. The current formulation used in patients delivers BCNU; this NCDDG now has compelling evidence that other drugs-including drugs that would be difficult to administer by other methods-might be even more effective. During the last 9 years, this Program developed new experimental techniques for studying the transport and distribution of agents released from polymer implants into the brain and mathematical models of drug transport. Experimental data and models have allowed us: A) to categorize drugs molecules in terms of their "penetrability" and B) to relate drug distribution in the brain to measurable, predictable properties of the drug molecule. Our mathematical models have been used to develop better methods for BCNU delivery and to design new drugs that are improved for interstitial delivery because of their broader distribution in the brain. The objectives of this renewal project will build upon this progress. The hypotheses to be tested are: A) that drug distribution can be optimized by chemical coupling to biocompatible carriers with defined architecture and B) that multi-drug therapies will be more effective than single drugs. In addition, our mathematical models will be compared to measurements obtained in animals and, eventually, in patients receiving polymer-based therapy (with Project 4). The specific aims are: 1. to examine the kinetics of distribution of multi-drug combinations and drug-polymer conjugates; 2. To develop mathematical models of the brain that allow prediction of drug distribution during multi-drug and drug-conjugate therapy; and 3. to develop methods for predicting concentrations maps in the human brain assessed on MR images and microdialysis. Our Program will interact with all of the other NCDDG Programs. With Program 1, we will correlate pharmacokinetics and local distribution with efficacy and toxicity. We will use the best polymer formulations produced by Program 2 and Core B. We will provide all Programs with guidance in polymer design and drug selection, based on our models. We will collaborate with Program 4 on the development of engineered drugs that are specifically designed for intracranial delivery. And we will work with Program 5 by studying patterns of cytokine distribution and elimination during paracrine delivery in the brain.